Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β

Al-Mulla, Fahd; Bitar, Milad S.; Al-Maghrebi, May; Behbehani, Abdulla I.; Al-Ali, Waleed; Rath, Oliver; Doyle, Brendan; Tan, Kit Yee; Pitt, Andrew and Kolch, Walter (2011). Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β. Cancer Research, 71 (4), pp. 1334-1343.

Abstract

Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor ?B signaling that represses tumor invasion and metastasis. Glycogen synthase kinase-3ß (GSK3ß) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show that RKIP binds GSK3 proteins and maintains GSK3ß protein levels and its active form. Depletion of RKIP augments oxidative stress-mediated activation of the p38 mitogen activated protein kinase, which, in turn, inactivates GSK3ß by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3ß inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and ß-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3ß expression. These findings reveal the RKIP/GSK3 axis as both a potential therapeutic target and a prognosis-based predictor of cancer progression.

Publication DOI: https://doi.org/10.1158/0008-5472.CAN-10-3102
Divisions: Life & Health Sciences > Pharmacy
Additional Information: ©2011 AACR.
Uncontrolled Keywords: animals,carcinoma,cultured cells,colorectal neoplasms,disease progression,enzyme stability,glycogen synthase kinase 3,humans,mice,knockout mice,oxidative stress,phosphatidylethanolamine binding protein,phosphorylation,protein binding,signal transduction,up-regulation,Cancer Research,Oncology
Published Date: 2011-02-15

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